Diabetes mellitus is a family of disorders characterized by chronic hyperglycemia and the development of long-term vascular complications. This family of disorders includes type 1 diabetes (T1D), type 2 diabetes, gestational diabetes, and other types of diabetes.
Immune-mediated (type 1) diabetes (or insulin dependent diabetes mellitus, IDDM, T1D) is a disease of children and adults for which there currently is no adequate means for prevention or cure. T1D represents approximately 10% of all human diabetes. The disease is characterized by an initial leukocyte infiltration into the pancreas that eventually leads to inflammatory lesions within islets via a process called “insulitis.”
T1D is distinct from non-insulin dependent diabetes (NIDDM) in that only the T1D form involves specific destruction of the insulin producing beta cells of the islets of Langerhans. The destruction of beta cells appears to be a result of specific autoimmune attack, in which the patient's own immune system recognizes and destroys the beta cells, but not the surrounding alpha cells (glucagon producing) or delta cells (somatostatin producing) that comprise the pancreatic islet. The progressive loss of pancreatic beta cells results in insufficient insulin production and, thus, impaired glucose metabolism with attendant complications.
The factors responsible for T1D are complex and thought to involve a combination of genetic, environmental, and immunologic influences that contribute to the inability to provide adequate insulin secretion to regulate glycemia.
The natural history of T1D prior to clinical presentation has been extensively studied in search of clues to the etiology and pathogenesis of beta cell destruction. The prediabetic period may span only a few months (e.g., in very young children) to years (e.g., older children and adults). The earliest evidence of beta cell autoimmunity is typically the appearance of various islet autoantibodies. Metabolically, the first signs of abnormality can be observed through intravenous glucose tolerance testing (IVGTT). Later, as the disease progresses, the oral glucose tolerance test (OGTT) typically becomes abnormal. T1D manifests with continued beta cell destruction and insulinopenia.
T1D occurs predominantly in genetically predisposed subjects. Concordance for T1D in identical twins is 30-50% with an even higher rate of concordance for beta cell autoimmunity, as evidenced by the presence of islet autoantibodies in these individuals (Pyke, (1979)). While these data support a major genetic component in the etiopathogenesis of T1D, environmental or non-germline genetic factors must also play important pathologic roles. Environmental factors proposed to date include viral infections, diet (e.g., nitrosamines in smoked meat, infant cereal exposure), childhood vaccines, lack of breast-feeding, early exposure to cows' milk, and aberrant intestinal functioning (Vaarala et al. (2008)). Hence, while the list of potential environmental agents for T1D is large, the specific environmental trigger(s) that precipitate beta cell autoimmunity remain elusive.
Although pre-diabetogenic T cells (bearing TCR specificity for pancreatic islet cell related antigens) are essential for T1D onset, studies in rodent models (Shoda et al. 2005) and patients (Metcalfe et al. (2001); Redondo et al. (2001); Hyttinen et al. (2003)) suggest that T1D may be prevented by inhibiting their acquisition of diabetogenic effector functions. Antigen presenting cells (APC), in particular dendritic cells (DC), maintain immune homeostasis by providing signals sufficient to activate pathogen-specific naïve T lymphocytes while being able to induce tolerance in naïve T cells specific to self-tissues and commensal bacteria. APC modulate immune responses by providing antigen presentation, necessary co-stimulatory signals, and appropriate cytokine environment.
A peaceful mutualism exists between resident gut bacteria and the mammals in which they reside: the host provides food for the commensal bacteria, which in turn provide nutrients to the host by metabolizing otherwise indigestible food. In addition, a dynamic equilibrium also exists between resident gut flora and the development of the mammalian immune system. In particular, Th17 effector functions are induced by resident commensal bacteria, and subsequently regulate the composition of bacteria residing within the gut (Curtis et al. (2009) and Ivanov et al. (2008)).
Studies have shown that modulation of gut composition can alter onset of T1D (Vaarala et al. (2008)). Moreover, it has been recently demonstrated that distinct, naturally occurring microbial communities reside within the gut of Bio-breeding diabetes prone (BBDP) and Bio-breeding diabetes resistant (BBDR) rats (Roesch et al. (2009), and within the subset of female non-obese diabetic (NOD) mice naturally resistant to T1D compared to susceptible syngeneic mice (Kriegel et al. (2011)).
In terms of gut microbial regulation, APC prime T lymphocyte effector functions, maintain mutualistic communities while eliminating those perceived as pathogens. While IL17A (hereafter, IL17) effector function by T lymphocytes is important in microbial gut community regulation (Happel et al. (2005); Higgins et al. (2006); Murphy et al. (2003)), the role of APC primed IL17 production in the context of T1D, is less clear as it has been correlated with both onset and resistance (Nikoopour et al. (2010); Bending et al. (2009); Martin-Orozco et al. (2009)).
Notably, increased natural segregation of gut residing Segmented Filamentous Bacteria (SFB) (Kriegel et al. (2011)) and oral feeding of Lactobacillus johnsonii N6.2 (LjN6.2) (Valladares et al. (2010)) were sufficient to confer T1D resistance to T1D susceptible rodent strains. The resistance to T1D mediated by LjN6.2 and SFB was correlated to a Th17 bias (Kriegel et al. (2011); Lau K et al. (2010)). Although DC prime naïve T lymphocytes can interact with resident gut flora communities directly (Grainger et al. (2010)), how distinct microbes can contribute to APC priming of diabetogenic T lymphocytes effector functions is poorly understood.
The NOD is a well-established mouse model of T1D, with destructive leukocytic infiltration of pancreatic islets, followed by insulin insufficiency in >80% of females. The NOR mouse, a recombinant congenic mouse strain, possesses 88% genetic identity with the NOD mouse and also develops leukocytic infiltrations within the pancreatic vasculature. However, unlike NOD mice, the leukocytic infiltrations in NOR do not typically progress to insulitis (i.e., intra-islet invasion), rendering NOR mice T1D free.
As noted above, one of the numerous factors that have been considered in the context of unraveling the complex etiology of T1D is intestinal functioning, including the interaction of intestinal microflora. The presence of a commensal intestinal microbiota in infancy is critical and well documented for numerous physiologic processes including growth, angiogenesis, optimization of nutrition, and stimulation of various arms of the innate and adaptive immune systems. However, similar studies in T1D are limited. In rodent models of T1D, the disease is likely to develop under germ free conditions. Diabetes prone rats (BB-DP) subjected to cesarean derivation develop accelerated disease (Like et al. (1991)). In terms of using such information to proactively modulate diabetes formation, antibiotic treatments to BB-DP rats after weaning (Brugman et al. (2006)) prevents diabetes, whereas with the NOD mouse, a decreased frequency of T1D was observed with the administration of doxycycline (Schwartz et al. (2007)). Probiotic treatment of NOD mice prevents the onset of T1D (Calcinaro et al. (2005); Yadav et al. (2007)). Similarly, a low fat diet with Lactobacillus strains reduced insulin-dependent diabetes in rats (Matsuzuki et al. (2007)). Antibiotics can prevent T1D in diabetes-prone rats (Brugman et al. (2006)) and in NOD mice (Schwartz et al. (2006)). The incidence of diabetes in NOD mice increases in a germ-free environment (Suzuki et al. (1987); Wicker et al. (1987)). Freund's adjuvant, which contains mycobacteria, also protects NOD mice and the BB-DP rat against diabetes (Sadelain et al. (1990 a and b) and McInerney et al. (1991)). The specific mechanisms of how such therapies modulate disease are unclear.
T1D is currently managed by the administration of exogenous human recombinant insulin. Although insulin administration is effective in achieving some level of euglycemia in most patients, it does not prevent the long-term complications of the disease including ketosis and damage to small blood vessels, which may affect eyesight, kidney function, and blood pressure and can cause circulatory system complications.
Although knowledge of the immune system has become much more extensive in recent years, the precise etiology of T1D remains a mystery. Furthermore, despite the enormously deleterious health and economic consequences, and the extensive research effort, there currently is no effective means for controlling the formation of this disease.
In addition to T1D, other autoimmune diseases, for example, lupus, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, etc. also have a genetic component and an environmental component. One of those environmental components is the interaction between bacteria residing in a subject's body with the subject's immune system. These interactions initially involve the dendritic cells. In addition, autoimmune diseases are promoted by T lymphocytes that acquire autoimmune effector functions, usually mediated through interactions with antigen presenting cells, for example, dendritic cells, and the environment generated by them. The contributions of the environmental factors have not been studied to extent that they can be used in prevention and/or treatment of the autoimmune diseases.